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Platinum-induced lipid reprogramming and tumor immune microenvironment in SCLC

SCLC 中铂诱导的脂质重编程和肿瘤免疫微环境

基本信息

批准号：
10657660
负责人：
Lingtao Jin
金额：
$ 35.45万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657660
关键词：
Acute Allografting Antigen Presentation Antigen-Presenting Cells Attenuated Biological Assay Cell physiology Chronic Clinical Combination immunotherapy Combined Modality Therapy Complex Dendritic Cells Development Enzymes Exhibits Fatty Acids Functional disorder Genetic Genetically Engineered Mouse Glutamine Goals Immune Immune Evasion Immune System Diseases Immune checkpoint inhibitor Immune response Immunosuppression Immunotherapeutic agent Immunotherapy Impairment Infiltration Lipids Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator Metabolic Metabolism Mitochondria Modeling Molecular Mutation Nature PD-1/PD-L1 PD-L1 blockade Peroxisome Proliferator-Activated Receptors Phenotype Pilot Projects Platinum Play Proteomics Regulation Respiration Role Shapes Signal Transduction Survival Rate T cell infiltration TP53 gene Technology Testing Therapeutic Tumor Antigens Tumor Immunity Tumor-Derived Validation Work antagonist anti-PD-1 anti-PD-L1 anti-PD-L1 antibodies anti-tumor immune response arginase cancer immunotherapy checkpoint therapy chemotherapy efficacy evaluation exosome fatty acid metabolism humanized mouse immune checkpoint blockers immune function immunogenicity immunoregulation improved in vivo Model inhibitor lipid metabolism lipidomics long chain fatty acid metabolomics neoplasm immunotherapy patient subsets pharmacologic pre-clinical programs response small cell lung carcinoma therapeutic target transcriptome sequencing tumor tumor microenvironment tumor-immune system interactions uptake

项目摘要

PROJECT SUMMARY Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer with a five-year survival rate of less than 5%. Immune checkpoint inhibitor (ICI) therapy such as anti-PD1/PD-L1 antibodies has demonstrated unprecedented clinical activity in several difficult-to-treat cancers, with durable responses in a subset of patients. Anti-PD-L1 antibodies such as atezolizumab, for example, have been recently received FDA approval as first line treatment in combination with platinum-based chemotherapy for SCLC; however, the efficacy seems modest. The mechanistic basis for the modest efficacy of immune checkpoint inhibitor in SCLC remains unknown but mounting evidence suggests that the immunosuppressive nature of tumor microenvironment dictates the poor efficacy of immunotherapy in SCLC. In addition, the potential impact of platinum-based chemotherapy on anti- tumor immune response may also play an important role in determining the efficacy of immunotherapy. Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment induces immune dysfunctional tumor-infiltrating DC (TIDC), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we found that fatty acids-carrying tumor derived exosomes (TDEs) induce immune dysfunctional DC to promote immune evasion. We also discover that platinum, the front-line treatment for SCLC, further exacerbates TDE-induced DC dysfunction through reprograming of glutamine-lipid metabolism in SCLC. Mechanistically, platinum rewires glutamine metabolism to promote fatty acid synthesis, leading to enrichment of long chain fatty acids in TDEs. As a result, TIDCs uptake TDEs with large amount of fatty acids that activates peroxisome proliferator activated receptor  (PPAR) signaling, leading to aberrant lipid accumulation and elevated FAO activity, which culminates in the induction of immunosuppressive enzyme arginase 1 (Arg1) and consequently dysfunction in TIDCs. Genetic depletion or pharmacologic inhibition of PPAR effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARlies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target. As such, targeting PPAR can be exploited to improve anti-cancer immunotherapy. We will test our hypothesis through the following aims: Aim 1: To explore how TDEs activate PPAR and induce Arg1 to drive DC dysfunction. Aim 2: To investigate how platinum rewires glutamine metabolism in SCLC to induce dendritic cell dysfunction and immune evasion. Aim 3: To evaluate the efficacy of Chemo/anti-PD- L1/PPAR inhibitor combination in SCLC.

项目总结